Substituted 5-(2-(2-aryl-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxoles

ABSTRACT

A process is disclosed for obtaining the R,R isomer of: ##STR1## wherein R 1  and R 2  may be one or more groups which may be the same or different and are selected from the group consisting of hydrogen, C 1  to C 4  alkyl, C 1  to C 4  alkoxy, hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, C 1  to C 4  thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consisting of ##STR2## wherein R&#39; is hydrogen; R 2  and R 3  may be the same or different and are selected from the group consisting of hydrogen and C 1  to C 4  alkyl; R 5  and R 6  are selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, --CH 2  OCH 2  COOR 7  and --CH 2  OCH 2  CH 2  OR 7  where R 7  is hydrogen or C 1  to  4  alkyl; except that R 5  and R 6  may not both be hydrogen; and the asterisks denote asymmetric carbon atoms; said process comprising the steps of: 
     (a) reacting Mosher&#39;s acid with a compound of formula I to attach a group of the formula ##STR3##  at the N-9 position of a mixture of (+) and (-) enantiomers of said compound to form a new pair of diastereoisomers; and 
     (b) separating said new pair of diastereoisomers by HPLC and recovering the R,R isomer. 
     The process is based on reacting Mosher&#39;s acid with the compound of formula I and thereafter using HPLC to separate the R,R isomer.

This is a divisional of application Ser. No. 07/742,409, filed Aug. 8,1991; now U.S. Pat. No. 5,151,439 which is a divisional of Ser. No.07/519,192, filed May 4, 1990 now U.S. Pat. No. 5,061,727.

The present invention relates to novel 1,3-benzodioxole compounds whichhave antidiabetic and/or anti-hyperglycemic properties in mammals. Moreparticularly it relates to novel substituted5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles. Thepresent invention also relates to pharmaceutical compositions comprisingthese compounds, methods for the preparation of these compounds, as wellas methods for the use of these compounds in treating diabetes and/orhyperglycemia and/or obesity in mammals.

BACKGROUND OF THE INVENTION

It is well known to employ medicinal agents in the treatment of personssuffering from diabetes, hyperglycemia and obesity

Ainsworth et al, U.S. Pat. No. 4,478,849, disclose secondary aminecompounds having the general formula (I): ##STR4## wherein R₁ is ahydrogen, fluorine or chlorine atom or a hydroxyl, hydroxymethyl,methyl, methoxyl, amido, formamido, acetamido, methylsulfonylamido,nitro, benzyloxy, methylsulfonylmethyl, ureido, trifluoromethyl, ormethoxybenzylamino group; R₂ is a hydrogen, fluorine or chlorine atom ora hydroxyl group; R₃ is a hydrogen or chlorine atom or a hydroxyl group;R₄ is a carboxylic acid group or a salt, ester or amide thereof; R₅ is ahydrogen, chlorine or fluorine atom or a methyl, methoxyl, or hydroxylgroup or a carboxylic acid group or a salt, ester or amide thereof; R₆is a hydrogen atom or a methyl or propyl group; X is an oxygen atom or abond; and Y is an alkylene group of up to 6 carbon atoms or a bond,which have anti-obesity and/or anti-hyperglycemic activity

Ainsworth et al, U.S. Pat. No. 4,396,627, disclose secondary aminecompounds of the formula (II): ##STR5## wherein R₁, R₂ and R₃ are asdefined in relation to formula (I) or each independently represents abromine atom; R₄ is an alkyl group of 1 to 10 carbon atoms substitutedby a hydroxyl, lower alkoxyl, oxo, lower acyloxy or OCH₂ CO₂ H group orlower alkyl ester thereof; R₅ is a hydrogen, chlorine or fluorine atomor a methyl, methoxyl or hydroxyl group or a carboxylic acid group or asalt, ester or amide thereof; R₆ is a hydrogen atom or a methyl, ethylor propyl group; R₇ is a hydrogen atom or a methyl, ethyl, or propylgroup; X is an oxygen atom or a bond; and Y is an alkylene group of upto six carbon atoms or a bond; which are useful in reducing high bloodglucose and lipid levels in humans and animals.

Ainsworth et al, U.S. Pat. No. 4,385,066 disclose arylethanol aminederivatives of the formula (III): ##STR6## wherein R₁ and R₂ arehydrogen or methyl; n is 1, 2 or 3; and Z is alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, halogen or hydrogen; useful intreating obesity and/or hyperglycemia and/or inflammation in mammals.

Ferris, U.S. Pat. No. 4,341,793 discloses secondary amine compounds ofthe formula (IV): ##STR7## wherein A₁ and A₂ are hydrogen or methyl; nis 1, 2 or 3; and R is hydrogen, chlorine, bromine, hydroxy, nitro,amino or trifluoromethyl; which are useful as antihyperglycemia agentsor anti-obesity agents.

Smith et al., U.S. Pat. No. 4,309,443, disclose cinnamic acidderivatives of the formula (V): ##STR8## wherein R₁ and R₂ and R₃ are asdefined in relation to formula (II); R₄ is a hydrogen, chlorine orfluorine atom or a methyl, methoxyl or hydroxyl group or a carboxylicacid group or a salt, ester or amide thereof; R₅ and R₆ are a hydrogenatom or methyl group; R₇ and R₈ are a hydrogen atom or methyl or ethylgroup; X is an oxygen atom or a bond; and Y is an alkylene group of upto 5 carbon atoms; which have been found to possess anti-obesity and/oranti-hyperglycemia activity.

Duckworth, U.S. Pat. No. 4,382,958, disclose secondary aminecompositions of the formula (VI): ##STR9## wherein each of R₁ and R₂ arehydrogen, methyl or ethyl; R₃ is hydrogen, fluorine, chlorine, bromineor trifluoromethyl; each of R₄ and R₅ is hydrogen, fluorine, chlorine,bromine, alkyl having 1 to 6 carbon atoms, or alkoxy having 1 to 6carbon atoms; n is 1 or 2; and X is straight or branched alkylene having1 to 12 carbon atoms; which are anti-obesity, hypoglycemia,anti-inflammatory and platelet aggregation inhibiting agents.

Ainsworth et al., U.S. Pat. No. 4,654,371, disclose secondary aminecompounds of the formula (VII): ##STR10## wherein R₁₅ is a hydrogen atomor a methyl group; R₁₆ is a hydrogen atom or a methyl group and m is 1;useful in treating obesity and hyperglycemia in humans or animals

Ikezaki et al., U.S. Pat. No. 4,490,392 disclose benzylalcoholderivatives of the formula (VIII): ##STR11## wherein R is hydroxy,benzyloxy, halogen or alkoxy having 1 to 4 carbon atoms and Ring A ismonomethoxyphenyl, dimethoxyphenyl, trimethoxyphenyl or3,4-methylenedioxyphenyl; which are useful as anti-diabetic agents.

Ferris, U.S. Pat. No. 4,432,993 discloses 2-(2-benzofuranyl)ethanolaminederivatives of the formula (IX): ##STR12## wherein R₁ is hydrogen ormethyl; R₂ is hydrogen or methyl; R₃ is hydroxy, hydroxy(C₁ -C₆)alkoxy,benzyloxy or a group X-Y-Z wherein (i) X is a bond or oxygen, Y is a C₁-C₆ straight or branched alkylene, and Z is hydrogen or carboxy; or (ii)X is a bond or --O--CH₂ --, Y is a C₂ -C₆ straight or branchedalkenylene and Z is carboxy; R₄ is hydrogen, hydroxy, halogen, C₁ -C₆alkyl or C₁ -C₆ alkoxy; and n is 1, 2 or 3; which have anti-obesity,hypoglycemia, anti-inflammatory, and platelet-aggregation inhibitingactivity.

Ainsworth et al., U.S. Pat. No. 4,338,333 disclose ethanaminederivatives of the formula (X): ##STR13## wherein R₁, R₂ and R₃ are asdefined in relation to formula (I) or each independently represent abromine atom; R₄ is a hydrogen atom or methyl group; R₅ is a hydrogenatom or methyl group; R₆ is a hydrogen, fluorine or chlorine atom or amethyl, methoxyl or hydroxy group; X is an oxygen atom or a bond; Y isan alkylene group of up to 6 carbon atoms or a bond; and Z is analkylene, alkenylene or an alkynylene group of up to 10 carbon atoms;which possess anti-obesity and anti-hyperglycemia properties.

Ikezaki et al., U.S. Pat. No. 4,032,575 disclose benzylalcohol aminederivatives of the formula (XI): ##STR14## wherein Ring A ismonohydroxyphenyl; which induce a decrease in blood sugar levels whenRing A is 2-hydroxyphenyl.

Holloway et al., U.S. Pat. No. 4,772,631, disclose phenoxyacetic acidethers of the formula (XII): ##STR15## wherein R₁ is hydrogen orfluorine; R₂ and R₃ are hydrogen or alkyl having 1 to 3 carbon atoms; Zis CH₂ OH or a group --COR₄ in which R₄ is OH, NH₂ or alkoxy having 1 to6 carbon atoms; which are useful in treating obesity and relatedconditions.

Philion, U.S. Pat. No. 4,751,246 disclose benzenemethanol and ethylaminecompounds of the formula (XIII): ##STR16## wherein R₁, R₂ and R₃ areindependently hydrogen or lower alkyl; n is an integer from 1 to 3; Aris phenyl, methylenedioxyphenyl or phenyl having from 1 to 3substituents selected from the group consisting of halo, lower alkyl,hydroxy and lower alkoxy; R is lower alkyl; and Y is hydrogen, loweralkyl, lower alkoxy, lower alkyl; lower alkanoyl, aroyl, benzenesulfonylor toluenesulfonyl; which are useful as anti-hypertensive agents.

It has now been discovered that a group of novel substituted5-(2-((2-aryl-2-hydroxyethyl)amino) propyl)-1,3-benzodioxoles possessvastly increased anti-hyperglycemia and anti-obesity properties withgreater β₃ selectivity in comparison with the prior art compounds. Thecompounds are therefore useful in treating diabetes, hyperglycemia andobesity, exhibiting minimal side effects, i.e. heart rate increase andmuscle tremor in humans and animals, when formulated into pharmaceuticalcompositions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a comparison of the selectivity between a compound of thepresent invention and a prior art compound.

FIG. 2 shows a comparison of the selectivity between a compound of thepresent invention and a prior art compound.

SUMMARY OF THE INVENTION

According to the present invention there are provided new compounds ofthe formula (XIV): ##STR17## wherein R₁ and R₄ may be one or more groupswhich may be the same or different and are selected from the groupconsisting of hydrogen, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, hydroxy,halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, C₁ toC₄ thioalkyl, sulfonyl and sulfinyl; X is a divalent radical consistingof ##STR18## wherein R' is selected from the group consisting ofhydrogen, C₁ to C₄ alkyl and C₁ to C₄ acyl and Y is selected from thegroup consisting of carbonyl and thiocarbonyl; R₂ and R₃ may be the sameor different and are selected from the group consisting of hydrogen andC₁ to C₄ alkyl; R₅ and R₆ are selected from the group consisting ofhydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, --CH₂ OCH₂ COOR₇ and--CH₂ OCH₂ CH₂ OR₇, where R₇ is hydrogen or C₁ to C₄ alkyl; with theprovision that R₅ and R₆ may not both be hydrogen; and thepharmaceutically acceptable salts and esters thereof, the enantiomersthereof, the racemic mixtures thereof and the diastereomeric mixturesthereof.

The compounds of the above formula have centers of asymmetry at thecarbon atoms marked with an asterisk. The compounds may, therefore,exist in at least two and often four stereoisomeric forms. The presentinvention encompasses all stereoisomers of the compounds whether freefrom other stereoisomers or admixed with other stereoisomers in anyproportion and thus includes, for instance, racemic mixture ofenantiomers as well as the diastereomeric mixture of isomers.

Preferably both asymmetric carbon atoms have the R absolutestereochemical configuration.

The absolute configuration of any compound may be determined byconventional X-ray cyrstallography.

The preferred compounds are(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, dimethyl ester;(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diethyl ester;(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diisopropyl ester;(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, disodium salt;(R*,R*)-(±)((5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-diyl)-bis-(methyleneoxy)bisacetic acid, dimethyl ester;(R*,R*)-(±)-3-(2-(2,2-bis(2-hydroxyethoxy)methyl)-1,3-benzodioxole-5-yl)-1-methylethyl)5-(3-chlorophenyl)-2-oxazolidinone;(R*,R*)-(±)-((5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-diyl)bis(methyleneoxy)) bis aceticacid, dimethyl ester;(R*,R*)-(±)alpha-(((2-(2,2-bis(2-hydroxyethoxyl)methyl)-1,3-benzodioxole-5-yl)-1-methylethyl)amino)methyl)-3-chlorobenzenemethanol;and the optically active derivatives thereof.

Also according to the present invention there is provided a method oftreating diabetes and/or hyperglycemia and/or obesity in humans or othermammals which comprises administering to a human or other mammal anantiobesity effective amount or an anti-hyperglycemia effective amountof a compound of the resent invention.

Further, according to the present invention there are providedpharmaceutical compositions of matter comprising an effective amount ofthe compounds of the present invention in combination with apharmaceutically acceptable carrier; as well as a method for increasingthe content of lean meat in edible mammals, which comprisesadministering to edible mammals an effective amount of the compound.

Also according to the present invention there are provided processes forproducing the compounds of the present invention and a process for theresolution of the optical isomers of the present invention and salts andesters thereof.

DETAILED DESCRIPTION OF THE INVENTION

The disease diabetes mellitus is characterized by metabolic defects inproduction and utilization of glucose which result in the failure tomaintain appropriate blood sugar levels. The result of these defects iselevated blood glucose or hyperglycemia. Research on the treatment ofdiabetes has centered on attempts to normalize fasting and postprandialblood glucose levels. Treatments have included parenteral administrationof exogenous insulin, oral administration of drugs and dietarytherapies.

Two major forms of diabetes mellitus are now recognized. Type Idiabetes, or insulin-dependent diabetes, is the result of an absolutedeficiency of insulin, the hormone which regulates glucose utilization.Type II diabetes, or insulin-independent diabetes, often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type II diabetics are also obese.

The compounds of this invention were tested for hypoglycemic andanti-obesity activity according to the following procedure.

Obese mice (C57 B1/6J (ob/ob)), and/or diabetic mice (C57 B1/KsJ(db/db)) were obtained from Jackson Laboratories, Bar Harbor, Me. Obeserats (fa/fa) were obtained from Charles River Laboratories, Wilmington,Mass. Obese mice were 8 weeks of age and diabetic mice were 9 weeks ofage at the start of the test. Obese rats were 12-14 weeks of age at thestart.

The test compounds were dissolved in methanol, mixed with powderedPurina rodent chow on a weight of compound to weight of chow basis andthoroughly dried.

Groups of 6 control mice or rats received vehicle (methanol) treatedchow.

Groups of 6 test mice were fed ad libitum for up to seven weeks and foodconsumption was measured daily by weighing the food bins before andafter the addition of fresh chow. Thus, a 40 g mouse, fed the testcompound at a concentration of 0.02 percent of the diet, would receive adose of 20 mg/kg/day if it ate 4 g of chow per day.

Groups of 6 test rats were fed 25 g of chow per day for one month.Except for the first day or two, they consumed all their food each day.When these animals are fed ad libitum, they consume 26 g of chow per dayand the compounds have no effect on food consumption.

The mice or rats were weighed before the first treatment and once at theend of each indicated treatment period.

Blood samples were collected before the first treatment and once at theend of each indicated treatment period by retro-orbital puncture usingheparinized capillary tubes.

Plasma was separated by centrifugation in a Beckman microfuge for 5minutes. Plasma glucose concentrations were determined with the Beckmanglucose analyzer which uses a glucose oxidase method.

The results of these tests on representative compounds of this presentinvention and a comparative compound of the prior art appear in TableI-III.

                                      TABLE 1                                     __________________________________________________________________________    PLASMA GLUCOSE                                                                                            Plasma Glucose                                                     Type of                                                                            Dose  Levels in mg/100 ml                               Compound         Mice (% wt)                                                                              Weeks                                             __________________________________________________________________________                                0   1  4                                          (R*,R*)-(-/-)-5(2-((2-(3-chloro-                                                               ob/ob                                                                              0 (control)                                                                         233 283                                                                              275                                        phenyl))-2-hydroxyethyl)amino)                                                                      0.0005                                                                              270 164                                                                              179                                        propyl)-1,3-benzodioxole-2,2-                                                                       0.002 276 150                                                                              156                                        dicarboxylic acid, dimethyl                                                                         0.005 237 143                                                                              157                                        ester hydrobromide                                                                                        0  1  5  7                                                         db/db                                                                              0 (control)                                                                         445                                                                              496                                                                              543                                                                              56                                                             0.0005                                                                              452                                                                              162                                                                              164                                                                              17                                                             0.002 453                                                                              151                                                                              150                                                                              16                                                             0.005 447                                                                              148                                                                              138                                                                              18                                                                   0   1  4                                          (R*,R*)-(+/-)-5(2-((2-(3-chloro-                                                               ob/ob                                                                              0 (control)                                                                         232 273                                                                              245                                        phenyl)-2-hydroxyethyl)amino)                                                                       0.0005                                                                              218 193                                                                              240                                        propyl)-1,3-benzodioxole-2,2-di-                                                                    0.002 220 162                                                                              197                                        carboxylic acid, disodium salt                                                                      0.005 220 145                                                                              165                                                                    0  1  5  7                                                         db/db                                                                              0 (control)                                                                         445                                                                              496                                                                              543                                                                              56                                                             0.002 453                                                                              236                                                                              190                                                                              25                                                             0.005 452                                                                              155                                                                              145                                                                              16                                                                   0   5  10                                         (R*,S*)-(+/-)-5(2-((2-(3-chloro-                                                               ob/ob                                                                              0 (control)                                                                         227 284                                                                              213                                        phenyl)-2-hydroxyethyl)amino)                                                                       0.005 218 162                                                                              174                                        propyl)-1,3-benzodioxole-2,2-di-                                                                    0.02  219 135                                                                              153                                        carboxylic acid, dimethyl ester                                               __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________    CHANGE IN WEIGHT                                                                                            Change in weight in grams                                                                      Average Daily                                   Type of Mice                                                                         Dose  weeks            Food Consumption               Compound         or rat (% wt)                                                                              1   2   3    4   g/animal                       __________________________________________________________________________    (R*,R*)-(+/-)-5(2-((2-(3-(chloro-                                                              ob/ob  0 (control)                                                                         1.4 3.7 5.4  7.2 4.5                            phenyl)-2-hydroxyethyl)amino)                                                                         0.0005                                                                              0.5 2.2 3.2  5.2 5.6                            propyl)-1,3-benzodioxole-2,2-                                                                         0.002 -0.3                                                                              1.1 1.6  3.2 5.6                            dicarboxylic acid, dimethyl                                                                           0.005 -1.1                                                                              -0.7                                                                              -0.2 1.6 5.8                            ester hydrobromide                                                                             fa/fa  0 (control)                                                                         18  39  57   72  25                                                     0.0006                                                                              14  20  27   26  25                                                     0.002 1   2   3    4   25                                                     0.006 10  4   -15  -8  25                             (R*,R*)-(+/-)-5(2-((2-(3-chloro-                                                               ob/ob  0 (control)                                                                         3.1 5.6 7.0  9.3 4.5                            phenyl)-2-hydroxyethyl)amino)                                                                         0.002 1.6 4.1 4.7  7.3 5.2                            propyl)-1,3-benzodioxole-2,2-di-                                                                      0.005 0.2 1.6 2.4  4.7 5.9                            carboxylic acid, disodium salt                                                __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________    PLASMA GLUCOSE COMPARATIVE                                                                                    Plasma Glucose Level in mg/100 ml                                Type of Mice                                                                         Dose  Weeks                                         Compound           or rat (% wt)                                                                              0     1     2                                 __________________________________________________________________________    (R*,R*)-(+/-)-(4-(2-((2-(4-                                                                      ob/ob  0 (control)                                                                         233   183   252                               chlorophenyl)-2-hydroxyethyl)                                                                           0.0005                                                                              232   140   126                               amino)propyl)phenoxy)-acetic                                                                            0.0001                                                                              231   143   119                               acid, methyl ester**      0.005 231   137   138                                                  db/db  0 (control)                                                                         444   349   604                                                         0.005 440   138   132                               (R*,R*)-(+/-)-alpha-(((2-(1,3-                                                                   ob/ob  0 (control)                                                                         217   217                                     benzodioxol-5-yl)-1-methylethyl)                                                                        0.002 226   234                                     amino)methyl)-3-chlorobenzene-                                                                          0.005 227   175                                     methanol mixture with (R*,S*)-(+/-)                                                                     0.02  227   149                                     alpha-(((2-(1,3-benzodioxol-5-yl)-                                            1-methylethyl)amino)methyl)-3-                                                chlorobenzenemethanol                                                         (R*,S*)-(+/-)-alpha-(((2-(1,3-                                                                   ob/ob  0 (control)                                                                         217   217                                     benzodioxol-5-yl)-1-methylethyl)                                                                        0.002 228   204                                     amino)methyl)-3-chlorobenzene-                                                                          0.005 226   176                                     methanol                  0.02  229   128                                     __________________________________________________________________________     **prior art compound                                                     

The above Table I demonstrates that compounds of the present inventionand the pharmaceutically active salts thereof effectively lower bloodglucose levels when administered orally to genetic strains ofhyperglycemic mice which are animal models of type II diabetes. Thecompounds of the present invention are also seen, in Table II, todecrease weight gain when administered to genetic strains of mice andrats which are animal models of obesity. The exact mechanism by whichthey act is not known and the invention should not be construed aslimited to any particular mechanism of action.

As effective hypoglycemic and weight loss agents, these compounds areuseful for the treatment of hyperglycemia and obesity in Type IIdiabetes.

SELECTIVITY

β-Adrenergic receptors can be divided into β₂ and β₃ -subtypes.Activation of β₁ -receptors invokes increases in heart rate whileactivation of β₂ -receptors stimulates glycogen breakdown in muscle andthereby prevents glycogen synthesis. Activation of β₃ -receptorsstimulates lipolysis (the breakdown of adipose tissue triglycerides toglycerol and free fatty acids), and thereby promotes the loss of fatmass. Compounds that stimulate β₃ -receptors will have anti-obesityactivity. In addition, they have hypoglycemic or anti-diabetic activity,but the mechanism of this effect is unknown. A compound that selectivelystimulates β₃ -receptors, i.e., has little or no β₁ or β₂ -activity,will have the desired anti-diabetic and/or anti-obesity activity, butwithout the undesirable effects of increased heart rate (β₁ -effect) ormuscle tremor (β₂ -effect).

Selectivity of a compound was determined using the following procedures.The effect on heart rate (β₁ -effect) was determined using isolatedright atria. Guinea pig hearts were placed in a petri dish containingaerated Krebs Henseleit bicarbonate buffer (KHB) of the followingcomposition (mM): NaCl, 112.9: KCl, 4.7: KH₂ PO₄, 1.2: MgSO₄ 7H₂ O, 1.2:NaHCO₃, 25.0: CaCl₂, 2.4 and glucose, 11.5. The buffer was continuouslyaerated with 95% O₂ -5% CO₂. The right atria were dissected and clampedat one end to a tissue holder and electrode assembly (MRA Corp.) andtied at the other end to a force-displacement transducer (Gould-Statham,Burco). The tissues were maintained at 32° C. in a 50 ml capacity glasschamber (MRA Corp.) preloaded with 0.5 g tension. Heart rate wasmonitored by a Grass polygragh. After equilibration for two hours, theatria were exposed to 1 ×10⁻⁶ M isoproterenol for 5 minutes. Theincrease in heart rate was calculated and considered to be the maximumresponse for that tissue. The tissues were then washed and allowed toequilibrate for 90 minutes. Cumulative concentration-response curveswere then determined for each compound or vehicle. All responses weremeasured 5 minutes post-exposure. The responses of each compound wereexpressed as a percent of the response to isoproterenol. The molar EC₅₀value is the concentration of compound that gave 50% of its own maximumincrease in heart rate.

The β₂ -effect of the compounds was determined by their ability toinhibit the insulin-mediated incorporation of ¹⁴ C-glucose into glycogenin isolated muscle. Soleus muscle from mice were dissected, tied at eachend, and placed in a clamp to maintain tension. The clamped muscle wasadded to a vial that contained 2 ml of KHB with 1.5% bovine serumalbumin, 0.3 mU/ml insulin, 5mM (U⁻¹⁴ C) glucose, and the appropriateadditions of compound or vehicle. The vial was gassed with 95% O₂ 14 5%CO₂, capped, and the tissue incubated for one hour in a rotating waterbath at 37° C. The muscle was then removed, rinsed in ice-cold saline,blotted and weighed. It was then added to 1 ml of 30% KOH containing 5mg/ml of oyster glycogen, boiled for 10 minutes, and 0.4 ml of 2% Na₂SO₄ and 3.2 ml of 100% ethanol added. After standing overnight at 4° C.,the glycogen was pelleted by centrifugation, washed once with 66%ethanol, and repelleted. The pellet was dissolved in 1 ml of water andthe amount of radioactivity present determined by liquid scintillation.The decrease in radioactivity incorporated into glycogen by eachcompound is expressed as a percentage of the decrease obtained in thepresence of 1×10⁻⁷ M isoproterenol. The molar EC₅₀ value is theconcentration of compound that gave 50 percent of its own maximumpercentage decrease in insulin-mediated incorporation of ¹⁴ C-glucoseinto glycogen.

The β₃ -effect of the compounds was determined by their ability tostimulate adipocyte lipolysis. Rat epididymal fat pads were excised andplaced in 0.9% saline. Four grams of tissue were transferred to a flaskwith 20 ml of aerated Krebs-Henseleit bicarbonate (KHB) buffercontaining 3% fatty acid-free bovine serum albumin to which 75 mg ofcrude bacterial collagenase (Worthington) had been added. The tissue wasincubated for about 45 minutes at 37° C. with gentle shaking. The cellswere then washed three times with two volumes of KHB buffer, filteredthrough two layers of gauze, and brought to a final volume of 80 ml withKHB buffer. One ml aliquots of the cell suspension were added to plastictest tubes containing the appropriate additions of vehicle or compound.The cells were gassed for 1 minute with 95% O₂ -5% CO₂, capped, andincubated at 37° C. with continuous shaking for a total of 30 minutes.The reaction was stopped by adding 0.1 ml of 30% perchloric acid and 0.1ml of chloroform. After centrifugation, 0.5 ml of supernatant wastransferred to another test tube and neutralized with 0.04 ml of 3M K₂CO₃ -0.5M triethanolamine. The amount of glycerol generated from thehydrolysis of endogenous triglycerides was determined in acoupled-enzyme spectrophotometric assay. One-tenth milliliter of theneutralized extract was added to a test tube that contained 0.91 ml ofan assay mixture comprised of the following: 0.84M glycine, 0.42Mhydrazine sulfate, 4.2 mM EDTA, 0.9 mM β-NAD, 9.9 mM MgCl₂, 1 mM ATP, 17U of glycerophosphate dehydrogenase, and 4.3 U of glycerokinase. Thetest tubes were incubated for 40 minutes at 37° C. with constantshaking. The amount of NADH generated, which is proportional to theamount of glycerol, was determined from the increase in absorbance at340 nm. This value was corrected for the amount of NADH generated in theabsence of glycerol by incubating another aliquot of the neutralizedextract with the same assay mixture but without glycerokinase. The molarEC₅₀ value is the molar concentration of compound that gave 50% of thatcompound's own maximum rate of lipolysis.

FIG. 1 shows a comparison of the selectivity of a compound of thepresent invention CL₁(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, dimethyl ester hydrobromide with that of the corresponding priorart compound, BRL₁(R*,R*)-(±)-(4-(2-((2-(4-chlorophenyl)-2-hydroxyethyl)amino)propyl)phenoxy)-aceticacid, methyl ester (Beecham).

The results indicate that prior art compound BRL₁ has slightly greaterβ₃ potency, but that it also has more of the undesirable β₁ and β₂activities than does CL₁. FIG. 2 shows a comparison of the selectivityof a compound of the present invention CL₂(R*,R*)-(±)-5(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, disodium salt with the corresponding prior art compound, BRL₂(R*,R*)-(±)-alpha-(((2-(1,3-benzodioxol-5-yl)-1-methylethyl)amino)methyl)-3-chlorobenzenemethanol (Beecham).

The results indicate that CL₂ has slightly greater β₃ potency than doesBRL₂. CL₂ has no measurable β₁ activity whereas BRL₂ has significant β₁activity. CL₂ showed only minimal β₂ activity at 1×10⁻⁴ M whereas BRL₂was a full agonist with measurable activity at 1×10⁻⁷ M. Thus, both ofthe prior art compounds have more of the undesirable activities than dothe corresponding compounds of the present invention. These results aresummarized in Table IV below.

Table IV also summarizes the relative β₃ potencies of the resolved forms(RR and SS) of both the salt (CL₂) and methyl ester (CL₁). It can beseen from this data that the majority of activity resides with the RRisomer in each case. In the case of the disodium salts, the RRenantiomer is 47 fold more potent than the SS enantiomer. In the case ofthe methyl ester, the RR isomer is 36 fold more potent.

                  TABLE IV                                                        ______________________________________                                        β.sub.3 - SELECTIVITY COMPARISON                                                                          Glycogen                                              Lipolysis (β.sub.3)                                                                  R.A. Rate (β.sub.1)                                                                  Synthesis (β.sub.2)                     Compound (EC.sub.50, M)                                                                            (EC.sub.50, M)                                                                            (EC.sub.50, M)                               ______________________________________                                        Salts:                                                                        CL.sub.2 6 × 10.sup.-9                                                                       >10.sup.-3  >1 × 10.sup.-4                         CL.sub.3 3 × 10.sup.-9                                                                       --          --                                           CL.sub.4 1.4 × 10.sup.-7                                                                     --          --                                           BRL.sub.2 **                                                                           9 × 10.sup.-9                                                                       5.6 × 10.sup.-6                                                                     8 × 10.sup.-7                          Esters:                                                                       CL.sub.1 3 × 10.sup.-8                                                                       1.4 × 10.sup.-8                                                                     8 × 10.sup.-7                          CL.sub.5 8 × 10.sup.-9                                                                       --          --                                           CL.sub.6 2.9 × 10.sup.-7                                                                     --          --                                           BRL.sub.1 **                                                                           1.3 × 10.sup.-8                                                                       2 × 10.sup.-7                                                                     1.2 × 10.sup.-7                        Isoproterenol                                                                          1.2 × 10.sup.-8                                                                     1.5 × 10.sup.-9                                                                     8 × 10.sup.-9                          ______________________________________                                        β.sub.3 - SELECTIVITY ((EC.sub.50 - β.sub.1 or                      β.sub.2)/(EC.sub.50 - β.sub.3))                                             Selectivity for   Relative Selectivity                                        Lipolysis over:   (CL/BRL)                                                   Atria    Gly. Syn.                                                                              Atria      Gly. Syn.                                 ______________________________________                                        Salts:                                                                        CL.sub.2 >167,000   >16,700  >268     >188                                    BRL.sub.2 **                                                                           622        89                                                        Esters:                                                                       CL.sub.1 47         27       3.1      3.0                                     BRL.sub.1 **                                                                           15          9                                                        Isoproterenol                                                                            0.1        0.7                                                     ______________________________________                                         CL.sub.1 =                                                                    (R*,R*)(+/-)5(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-            1,3benzodioxole-2,2-dicarboxylic acid, dimethyl ester hydrobromide            CL.sub.2 =                                                                    (R*,R*)(+/-)5(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-            1,3benzodioxole-2,2-dicarboxylic acid, disodium salt                          BRL.sub.1 =                                                                   (R*,R*)(+/-)(4-(2-((2-(4-chlorophenyl)-2-hydroxyethyl)amino)propyl)-          phenoxy)acetic acid, methyl ester                                             BRL.sub.2 =                                                                   (R*,R*)(+/-)(4-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-          phenoxy)acetic acid, monosodium salt                                          ** = comparative example                                                      CL.sub.3 =                                                                    (R,R)(+/-)5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-         benzodioxole2,2-dicarboxylic acid, disodium salt.                             CL.sub.4 = (S,S)(+                                                            /-)5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-                benzodioxole2,2-dicarboxylic acid, disodium salt.                             CL.sub.5 =                                                                    (R,R)(+/-)5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-         benzodioxole2,2-dicarboxylic acid, dimethyl ester hydrobomide.                CL.sub.6 =                                                                    (S,S)(+/-)5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-         benzodioxole2,2-dicarboxylic acid, dimethyl ester hydrobomide.           

The results indicate that the compounds of the present invention, CL₂and CL₁ are 200 and 3 times more selective for lipolysis than are theprior art compounds, BRL₂ and BRL₁ respectively.

In addition to the abilities of the compounds of the present inventiondescribed hereinabove, some of the compounds of the present inventionare useful in the preparation of other compounds of the presentinvention.

The compounds of the present invention may generally be preparedaccording to the following process, the process comprising:

(a) reacting a compound of the formula ##STR19## with a ketalizingreagent of the formula ##STR20## wherein R₁, R₂, R₃ and R₄ are asabove-defined in relation to formula (XIV) and R₈ and R₉ are C₁ to C₄alkyl and Z is dihalomethylene, carbonyl or thiocarbonyl to produce acompound of the formula ##STR21## wherein R₁, R₂, R₃, R₄ and R₈ and R₉are as above defined; and, either

(b)(i) reacting the product of step (a) with a base followed by an acidand alcohol to produce a compound of the formula ##STR22## wherein R₁,R₂, R₃ and R₄ are as defined above and R₅ and R₆ are alkoxycarbonyl; andoptionally

(b)(ii) reacting the product of step (b)(i) with a reagent or reagentsfor converting the groups represented by R₅ and R₆ to carboxy,hydroxymethyl, --CH₂ OCH₂ COOR₇ and CH₂ OCH₂ --CH₂ OR₇ wherein R₇ ishydrogen or C₁ to C₄ alkyl; or

(c)(i) reacting the product of step (a) with a carbonyl reducing agentto form a compound of the formula ##STR23## wherein R₁, R₂, R₃ and R₄are as defined above; and

(c)(ii) reacting the product of (c)(i) with a reagent or reagents forconverting the CH₂ OH groups to a --CH₂ OCH₂ COOR₇ group or a --CH₂ OCH₂CH₂ OR₇ group wherein R₇ is as defined above; or

(c)(iii) reacting the product of step (c)(ii) with a base to produce acompound of the formula ##STR24## wherein R₁₀ and R₁₁ are selected froma --CH₂ OCH₂ COOR₇ group, a --CH₂ OCH₂ CH₂ OR₇, group and R₇ is as abovedefined.

Any conventional ketalizing reagents, bases, acids alcohols, reagentsfor converting to defined groups and carbonyl reducing agents known tothose skilled in the art may be employed and are contemplated by thepresent invention.

In preferred embodiments of the present invention, the followingreaction scheme may be employed. ##STR25##

In accordance with the above preferred reaction scheme2-(3-chlorophenyl)-2-hydroxyethylamine 1, and 3,4-dimethoxyphenylacetone2 are reacted with sodium cyanoborohydride in methanol, giving3-chloroalpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol 3 which is reacted with carbonyl diimidazole andtriethylamine in tetrahydrofuran, followed by separation of isomers,giving cyclized derivative 4 which is reacted with boron tribromide indichloromethane, giving(R*,R*)-(±)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)2-oxazolidinone 5. Compound 5 is then reacted withdiethyl dibromomalonate and anhydrous potassium carbonate in acetone,giving(R*,R*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diethyl ester 6 which is then reacted first with sodium hydroxidein ethanol and then with hydrogen chloride gas in methanol, giving theproduct (R*,R*)-(±) 5-(2-((2-(3-chlorophenyl)2-hydroxyethyl)-amino)propyl-1,3-benzodioxole-2, 2-dicarboxylic acid,dimethyl ester 7.

Compound 6 may alternatively be reacted with lithium borohydride inanhydrous tetrahydrofuran followed by reaction with sodium hydride andmethyl bromoacetate in anhydrous tetrahydrofuran, giving(R*,R*)-(±)-((5-(2((5-(3-chlorophenyl)-2-oxo)-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-diyl)bis(methyleneoxy))bis acetic acid, dimethyl ester 8 which is then reacted with lithiumborohydride in anhydrous tetrahydrofuran, giving(R*,R*)-(±)-3-(2-((2,2-bis((2-hydroxyethoxy)methyl)-1,3-benzodioxole-5-yl)-1-methylethyl)-5-(3-chlorophenyl)2-oxazolidinone9. Compound 9 is then refluxed with sodium hydroxide in ethanol, underargon, giving(R*,R*)-(±)-alpha-(((2-(2,2-bis((2-hydroxyethoxy)methyl)-1,3-benzodioxole-5-yl)-1-methylethyl)amino)methyl)-3-chlorobenzenemethanol10.

Alternatively compound 8 may be refluxed with sodium hydroxide inethanol, then neutralized and reacted with hydrogen chloride gas inmethanol to derive the product 11.

In another preferred embodiment, optical isomers of the presentinvention and the derivatives, salts and esters thereof may be resolvedby a process comprising: (a) attaching a chiral auxiliary group at theN-9 position of a mixture of (+) and (-) enantiomers of the compounds toform a new pair of diastereoisomers; (b) separating the new pair ofdiastereoisomers and recovering the new (+) or (-) enantiomer; and (c)converting the substantially pure new diastereoisomer into thecorresponding desired substantially pure (+) or (-) enantiomer of aderivative, salt or ester of the compound.

In a preferred embodiment, the following Scheme II may be employed.##STR26##

In accordance with the reaction sequence outlined in Scheme II,1,3-benzodioxole-2,2-dicarboxylic acid,5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino) propyl-, dimethyl ester,hydrobromide (R*, R*)-(±)-, (12) is treated with the acid chloridederived from (S)-(-)- -methoxy- -trifluoromethylphenylacetic acid(Mosher's acid). The diastereomeric amides 13 and 14 are separated bypreparative HPLC, treated with sodium hydroxide, and the disodium salts15 and 16 (pure enantiomers), respectively are isolated by reverse phasecolumn chromatography. Treatment of each salt with hydrobromic acid inmethanol yields each diester, 1,3-benzodioxole-2,2-dicarboxylic acid,5-(2-((-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl-, dimethyl ester,hydrobromide (R,R) (17) and 1,3-benzodioxole-2,2-dicarboxylic acid,5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl-, dimethyl esterhydrobromide (S,S) (18) respectively. In a similar manner, thecorresponding diethyl and diisopropyl esters can be prepared.

Repeating the above sequence starting with1,3-benzodioxole-2,2-dicarboxylic acid,5-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl-, dimethyl ester,hydrobromide (R*,S*)-(±) yields both enantiomers1,3-benzodioxole-2,2-dicarboxylic acid,5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl-, dimethyl ester,hydrobromide (R,S) and 1,3-benzodioxole-2,2-carboxylic acid,5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl-, dimethyl ester,hydrobromide (S,R) respectively. In a similar manner, the correspondingdiethyl and diisopropyl esters can be prepared.

Alternatively, the chiral synthesis of the compounds of the presentinvention may generally be prepared according to the following process,the process comprising;

(a)(i) reacting an optically active compound of the formula ##STR27##wherein R₂, R₃ and R₄ are as above defined in relation to formula (XIV)and R" is C₁ to C₄ alkyl with a compound of the formula ##STR28##wherein R₁ is as above defined in relation to formula (XIV) to produce acompound of the formula ##STR29## wherein R₁, R₂, R₃, R₄, and R" are asdefined above;

(b)(i) reacting the product of step (a)(i) with a cyclizing reagentfollowed by separating the diastereoisomers and recovering the new (+)or (-) enantiomer; or

(a)(ii) reacting an optically active compound of the formula ##STR30##wherein R₂, R₃, R₄ and R" are as above defined with an optically activecompound of the formula ##STR31## where R₁ is as above defined toproduce a compound of the formula ##STR32## wherein R₁, R₂, R₃, R₄ andR" are as defined above and

(b)(ii) optionally, reacting said compound with a cyclizing reagent toproduce a compound of the formula ##STR33## wherein R₁, R₂, R₃, R₄, Yand R" are as defined above, and

(c) recovering the substantially pure new enantiomers of steps (b)(i),(a)(ii) or (b)(ii) and if desired converting said substantially pure (+)or (-) enantiomer into the corresponding derivative, salt or ester ofthe compounds of the present invention.

Further, the present invention provides a process for producing theinitial reactant of the above process, having the general formula##STR34## wherein R₂ and R₃ may be the same or different and areselected from the group consisting of hydrogen and C₁ -C₄ alkyl and R"are independently selected from C₁ to C₄ alkyl and R⁴ is selected fromthe group consisting of hydrogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy,halogen, trifluoromethyl, carboxy, hydroxyalkyl, alkoxycarbonyl, C₁ toC₄ thioalkyl, sulfonyl and sulfinyl; the process comprising

(a) reacting a compound of the formula ##STR35## with a carboxylatingreagent to produce a compound of the formula ##STR36## wherein R₃ and R₄are as above defined, and

(b) reacting the product of step (a) with an alkylating agent to producea compound of the formula ##STR37## wherein R₃, R₄, and R" are as abovedefined, and

(c) reacting the product of step (b) with a selective reducing agent toproduce a compound of the formula ##STR38## wherein R₃, R₄, and R" areas above defined, and

(d) reacting the product of step (c) with a sulfonylating agent toproduce a compound of the formula ##STR39## wherein R₂, R₃, R₄, and R"are as above defined, and

(e) reacting the product of step (d) with an acid followed by hydrogenand palladium to produce said compound.

More specifically, the chiral synthesis may be carried out by performingthe synthetic reaction sequence outlined in Scheme III. L-DOPA 19 istreated with di-t-butyl-dicarbonate in dimethylformamide, giving(S)-N-(1-(1,1-dimethylethoxy)carbonyl)-3-hydroxy-L-tyrosine 20 which isreacted with methyl iodide and anhydrous potassium carbonate in acetone,giving (S)-N-(1,1-dimethylethoxy)carbonyl)-3,4-dimethoxy-L-phenylalaninemethyl ester 21 which is reduced with lithium borohydride giving(S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1-(hydroxymethyl)ethyl)carbonate 22, which is reacted with methanesulfonyl chloride andtriethylamine in methylene chloride, giving(S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1(((methylsulfonyl)oxy)methyl)ethyl)carbamate 23. Compound 23 is treated withtrifluoroacetic acid and then is reduced using 10% Pd/C and hydrogengiving (R)-3,4-dimethoxy- -methylbenzeneethanamine 24. The compound 24is treated with 3-chlorostyrene oxide 25 and N-(trimethylsilyl)acetamide giving a mixture of (R,S)- and(S,S)-3-chloro-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol 26. Reaction of 26 with carbonyl diimidazole andtriethylamine in tetrahydrofuran, followed by chromatographic separationof the diastereomers gives cyclized derivative 27, which is reacted withboron tribromide in dichloromethane, giving(R,R)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone28. Compound 28 is then reacted with diethyl dibromomalonate andanhydrous potassium carbonate in acetone, giving(R,R)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diethyl ester 29. Compound 29 is reacted with 5N sodium hydroxidein ethanol and then isolated by reverse phase chromatography to give(R,R)-1,3-benzodioxole-2,2-dicarboxylic acid,5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-, disodium salt15.

Alternatively, reacting compound 24 with (R)-3-chlorostyrene oxide,enantiomerically pure 15 is prepared. Enantiomerically pure epoxides canbe prepared by asymmetric reduction of the corresponding x-chloroketoneas described by Corey, J. Am. Chem, Soc., 109, 5551 (1987), followed bybase catalyzed closure to the epoxide. ##STR40##

The active compounds of the present invention may be orally administeredas a pharmaceutical composition, for example, with an inert diluent, orwith an assimilable edible carrier, or they may be enclosed in hard orsoft shell capsules, or they may be compressed into tablets, or they maybe incorporated directly with the food of the diet. For oral therapeuticadministration, these active compounds may be incorporated withexcipients and used in the form of tablets, pills, capsules, ampules,sachets, elixirs, suspensions, syrups, and the like. Such compositionsand preparations should contain at least 0.1 percent of active compound.The percentage of active compound in these compositions may, of course,be varied and may conveniently be between about 2 percent to about 60percent of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagewill be obtained.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.

When treating diabetes mellitus and/or hyperglycemia generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 1 milligram per kilogram of animal body weight, preferablygiven in divided doses two to six times a day, or in sustained releaseform. For most large mammals, the total daily dosage is from about 3.5milligrams to about 140 milligrams, preferably from about 3.5 milligramsto about 5 milligrams. In the case of a 70 kg adult human, the totaldaily dose will generally be from about 7 milligrams to about 70milligrams. This dosage regimen may be adjusted to provide the optimaltherapeutic response.

When treating obesity, in conjunction with diabetes and/orhyperglycemia, or alone, generally satisfactory results are obtainedwhen the compounds of the present invention are administered at a dailydosage of from 1 milligram to about 10 milligrams per kilogram of animalbody weight, preferably given in divided doses two to six times a day,or in sustained release form. For most large mammals, the total dailydosage is from about 35 milligrams to about 1,400 milligrams, preferablyfrom about 35 milligrams to about 50 milligrams. In the case of a 70 kgadult human, the total daily dose will generally be from about 70milligrams to about 700 milligrams. This dosage regimen may be adjustedto provide the optimal therapeutic response.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of the present invention also possess utility forincreasing lean meat deposition and/or improving lean meat to fat ratioin edible animals, i.e. ungulate animals and poultry.

Animal feed compositions effective for increasing lean meat depositionand for improving lean meat to fat ratio in poultry, swine, sheep,goats, domestic pets and cattle are generally prepared by mixing thecompounds of the present invention with a sufficient amount of animalfeed to provide from about 1 to 1000 ppm of the compound in the feed.

Animal feed supplements can be prepared by admixing about 75% to 95% byweight of a compound of the present invention with about 5% to about 25%by weight of a suitable carrier or diluent. Carriers suitable for use tomake up the feed supplement compositions include the following: alfalfameal, soybean meal, cottonseed oil meal, linseed oil meal, sodiumchloride, cornmeal, cane molasses, urea, bone meal, corncob meal and thelike. The carrier promotes a uniform distribution of the activeingredients in the finished feed into which the supplement is blended.It thus performs an important function by ensuring proper distributionof the active ingredient throughout the feed.

If the supplement is used as a top dressing for the feed, it likewisehelps to ensure uniformity of distribution of the active material acrossthe top of the dressed feed.

The prefered medicated swine, cattle, sheep and goat feed generallycontain from 0.01 to 400 grams of active ingredient per ton of feed, theoptimum amount for these animals usually being about 50 to 300 grams perton of feed.

The preferred poultry and domestic pet feeds usually contain about 0.01to 400 grams and preferably 10 to 400 grams of active ingredient per tonof feed.

For parenteral administration the compounds of the present invention maybe prepared in the form of a paste or a pellet and administered as animplant, usually under the skin of the head or ear of the animal inwhich increase in lean meat deposition and improvement in lean mean tofat ratio is sought.

In general, parenteral administration involves injection of a sufficientamount of the compounds of the present invention to provide the animalwith 0.001 to 100 mg/kg/day of body weight of the active ingredient. Thepreferred dosage for swine, cattle, sheep and goats is in the range offrom 0.001 to 50 mg/kg/day of body weight of active ingredient; whereas,the preferred dose level for poultry and domestic pets is usually in therange of from 0.001 to 35 mg/kg/day of body weight.

Paste formulations can be prepared by dispersing the active compound ina pharmaceutically acceptable oil such as peanut oil, sesame oil, cornoil or the like.

Pellets containing an effective amount of the compounds of the presentinvention can be prepared by admixing the compounds of the presentinvention with a diluent such as carbowax, carnuba wax, and the like,and a lubricant, such as magnesium or calcium stearate, can be added toimprove the pelleting process.

It is, or course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level which willprovide the increase in lean meat deposition and improvement in leanmeat to fat ratio desired. Moreover, it has been found that implants mayalso be made periodically during the animal treatment period in order tomaintain the proper drug level in the animal's body.

The method of the present invention has several advantages; for the petowner or veterinarian who wishes to increase leaness and trim unwantedfat from pet animals, the present invention provides the means by whichthis can be accomplished. For the poultry men and swine raisers, usingthe method of the present invnetion yields leaner animals which commandhigher prices from the meat industry.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following specific examples illustrate the present invention. Theyare not to be construed to limit the claims in any manner whatsoever.

EXAMPLE 1(R*,R*)-(±)-5-(2-((2-(3-Chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, dimethyl ester

To a mixture of 53.2 g of trimethylsilyl cyanide and 0.5 g of anhydrousaluminum chloride under argon is added dropwise 75.3 g of3-chlorobenzaldehyde at such a rate that the reaction temperature doesnot exceed 80° C. The mixture is stirred for 30 minutes, then filteredand washed with ether. The combined filtrate and wash is evaporated toan oil which is distilled on a Kugelrohr giving 107.4 g ofO-trimethysilyl-3-chloromandelonitrile (70°-77° C.) as a pale yellowliquid.

To a mixture of 34.7 g of sodium borohydride and 500 ml oftetrahydrofuran is added 104.6 g of trifluoroacetic acid over 40 minuteswith stirring in a 20° C. water bath. A 110 g portion ofO-trimethyl-silyl-3-chloromandelonitrile is added over 45 minutes,followed by 150 ml of tetrahydrofuran. The mixture is stirred overnightin the 20° C. water bath, then 500 ml of water is added dropwise withice bath cooling. The mixture is then stirred at room temperature for 1hour, filtered through diatomaceous earth, washed with tetrahydrofuranand the combined filtrate and wash are concentrated in vacuo until mostof the tetrahydrofuran is removed. A 250 ml portion of water and 150 mlof concentrated hydrochloric acid are added, the solution is heated on asteam bath for 1.5 hours, cooled and extracted twice withdichloromethane. The aqueous extracts are combined, made strongly basicwith 200 ml of 10N sodium hydroxide in a cooling bath and extracted fourtimes with dichloromethane. The dichloromethane extracts are combined,washed twice with water, dried and evaporated to a yellow oil. This oilis dissolved in ether, filtered through diatomaceous earth andevaporated to an oil. This oil is distilled on a Kugelrohr giving 58.73g of 2-(3-chlorophenyl)-2-hydroxyethylamine as thick orange oil.

A mixture of 4 g of 2-(3-chlorophenyl)-2-hydroxyethylamine, 4.53 g of3,4-dimethoxyphenylacetone, 2 g of sodium cyanoborohydride and 40 ml ofmethanol is stirred for 3 hours and then worked up giving 7.5 g of oil.This oil is purified by chromatography, eluting with hexane:ethylacetate (1:1), then ethyl acetate, giving 5.35 g of3-chloro-alpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol as thick yellowsyrup.

A mixture of 4.39 g of 3-chloro-alpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol, 4.5 g ofcarbonyldiimidazole, 13 ml of triethylamine and 45 ml of tetrahydrofuranare stirred overnight, then poured into water and extracted twice withethyl acetate. The extracts are combined, washed twice with 2Nhydrochloric acid, once with brine, dried and evaporated to an oil. Thisoil is chromatographed, eluting with hexane:ethyl acetate (3:1 to 2:1).Fractions 16-19 are combined and evaporated giving 2.02 g of a colorlesssyrup. To an ice cold solution of 1.71 g of this syrup in 70 ml ofdichloromethane is added dropwise 1.3 ml of boron tribromide. Themixture is stirred at 0° to 5° C. for 15 minutes, then at roomtemperature for 20 minutes, quenched with water and stirred for 20minutes. The dichloromethane layer is separated, washed with brine,dried and evaporated, giving 1.6 g of(R*,S*)-(±)-5-(3-chlorophenyl)-3-(2 -(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone as a foamy solid.

A mixture of 0.8 g of the above oxazolidinone, 0.74 g of diethyldibromomalonate, 1.2 g of anhydrous potassium carbonate and 20 ml ofacetone are stirred overnight with the addition of a few drops ofdiethyl dibromomalonate. The mixture is filtered, washed with acetoneand the combined filtrate and wash are evaporated to a yellow oil. Theoil is purified by flash chromatography, eluting with 5 percent acetonein toluene. The pure fractions are combined and evaporated, giving 766mg of(R*,S*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diethyl ester as a colorless oil.

A mixture of 636 mg of the above diethyl ester, 23 ml of 5N sodiumhydroxide and 44 ml of ethanol are heated at reflux under argonovernight, then cooled and evaporated. The solid residue is taken up inmethanol, placed in an ice bath and hydrogen chloride gas is passedthrough the solution for 3-4 minutes. This mixture is stirred for 1.5hours, then poured cautiously into saturated aqueous sodium bicarbonateand extracted with ethyl acetate. This ethyl acetate extract is washedwith brine, dried, filtered and evaporated to an oil. This oil ispurified by flash chromatography, eluting with ethyl acetate. The purefractions are combined and evaporated, giving 264 mg of the desiredproduct as a colorless oil.

EXAMPLE 2(R*,S*)-(±)-((5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,3-benzodioxole-2,2-diyl)bis(methyleneoxy)bisacetic acid, dimethyl ester

A mixture of 1.63 g of(R*,S*)-(±)-5-(2-(5(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diethyl ester and 2.5 g of lithium borohydride in 25 ml ofanhydrous tetrahydrofuran are reacted, giving 1.26 g of thecorresponding alcohol as a white foam.

A 590 mg portion of 60 percent sodium hydride is washed three times withhexane. To this is added under argon, 10 ml of dry tetrahydrofuran and,over 5 minutes, a solution of 1.24 g of(R*,R*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid in 10 ml of dry tetrahydrofuran. The solution is stirred for 5minutes, then 1.36 g of methyl bromoacetate is added over 10 minutes.After stirring overnight this mixture is poured into aqueous ammoniumchloride and extracted twice with ethyl acetate. The extracts arecombined, dried and evaporated to an oil which is purified bychromatography, giving 1.03 g of the desired product as a pale yellowoil.

EXAMPLE 3(R*,R*)-(±)-3-(2-(2,2-Bis((2-hydroxyethoxy)methyl)-1,3-benzodioxol-5-yl)-1-methylethyl)-5-(3-chlorophenyl)-2-oxazolidinone

A mixture of 420 mg of(R*,R*)-(±)-(5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,3-benzodioxole)-2,2-diyl)bis(methyleneoxy)bisacetic acid, dimethyl ester, 0.75 g of lithium borohydride and 10 ml ofanhydrous tetrahydrofuran are allowed to react for 1.5 hours, giving 340mg of the desired product as a milky film.

EXAMPLE 4(R*,R*)-(±)-((5-(2-(2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-diyl)bis(methyleneoxy)bisacetic acid, dimethyl ester

A mixture of 370 mg of(R*,R*)-(±)-(5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-diyl)bis(methyleneoxy)bisacetic acid, dimethyl ester, 9 ml of 5N sodium hydroxide and 19 ml ofabsolute ethanol are refluxed overnight, then cooled, acidified to pH 5with concentrated hydrochloric acid and evaporated to dryness in vacuo.The residue is dissolved in 20 ml of methanol, then saturated withhydrogen chloride gas and stirred for 1.5 hours. The mixture is pouredinto aqueous sodium bicarbonate and extracted twice with ethyl acetate.The extracts are combined, washed with brine, dried and evaporated. Theresidue is purified by flash chromatography, eluting with ethyl acetate,giving 220 mg of the desired product as a pale yellow thick oil.

EXAMPLE 5(R*,R*)-(±)-alpha-(((2-(2,2-bis((2-hydroxyethoxy)methyl)-1,3-benzodioxole-5-yl)-1-methylethyl)amino)methyl)-3-chlorobenzenemethanol

A mixture of 270 mg of(R*,R*)-(±)-3-(2-(2,2-bis((2-hydroxyethoxy)methyl)-1,3-benzodioxole-5-yl)-1-methylethyl)-5-chlorophenyl)-2-oxazolidinone,200 ml of ethanol and 5 ml of 5N sodium hydroxide are refluxed underargon for 8 hours, then poured into salty water and extracted twice withethyl acetate. The extracts are combined, washed with brine, dried andevaporated. The residue is purified by flash chromatography, elutingwith dichloromethane:methanol:ammonium hydroxide (250:35:5). Fractions 3and 4 are combined and evaporated, giving 170 mg of the desired productas a thick yellow oil.

EXAMPLE 6 1,3-Benzodioxole-2,2-Dicarboxylic Acid,5-(2-((2-(3-Chlorophenyl)-2-Hydroxyethyl)Amino)Propyl), Disodium Salt,(R*,R*)-(±)-

A solution of (1,3-benzodioxole-2,2-dicarboxylic acid,5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-, diethyl ester,(R*,R*)-(±)-, (550 mg 1.09 mmol), 5N NaOH (15 mL) and distilled water(15 mL) is heated at reflux under an argon atmosphere for 17 hours. Thesolution is cooled, and then acidified to pH 9 using concentrated HClcausing a copious amount of white solid to precipitate. The mixture isfiltered and the solid is washed with water. The combined filtrate andwater wash (53 mL) is loaded onto a column packed with C₁₈ reverse phasesilica gel (75 mL) which had first been washed with MeOH (150 mL) andthen a pH 8.5 solution and then the product is eluted using MeOH:water(1:1). Evaporation of the product-containing fractions yielded a yellowoil which became a powdery solid upon addition of MeOH. The solid wascollected and washed with ether to yield a dry white powder, 395 mg(78%).

EXAMPLE 7 1,3-Benzodioxole-2,2-Dicarboxylic Acid,5-(2-((2-(3-Chlorophenyl)-2-Hydroxyethyl)Amino)Propyl)-, Dimethyl Ester,Hydrobromide, (R*,R*)-(±)-

Absolute methanol (20 mL) is treated dropwise with distilled acetylbromide (20 drops) and the solution is stirred for 5 minutes. To thissolution is added(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, disodium salt (500 mg, 1.09 mmol) and the solution is stirred for24 hours at room temperature. The solution is evaporated to give toyield a brown oil which is dissolved in chloroform and filtered toremove sodium bromide. The chloroform is evaporated and ether is addedto the resulting brown oil to give a beige solid. The solid is collectedand washed with ether to give a dry powder (520 mg, 90%).Recrystallization from acetonitrile-ether yielded the analytical sample,mp 145°-147° C.

EXAMPLE 8 1,3-Benzodioxole-2,2-Dicarboxylic Acid,5-(2-((2-(3-Chlorophenyl)-2-Hydroxyethyl)Amino)Propyl)-, Disodium salt,(R,R) and 1,3-Benzodioxole-2,2-Dicarboxylic acid,5-(2-((-(3-Chlorophenyl)-2-Hydroxyethyl)Amino)Propyl)-, Disodium Salt,(S,S)

A solution of(R*,R*)-(±)-5-(2((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, dimethyl ester hydrobromide (1.00 g, 1.88 mmol), triethylamine(0.48 g, 4.71 mmol) and (S)-(-)-2-trifluoromethyl-2-methoxyphenylacetylchloride (0.54 g, 2.26 mmol) in 10 mL of methylene chloride is stirredat room temperature for 3 days. The yellow solution is diluted with 50mL of ether and washed sequentially with 2N HCl, aqueous sodiumbicarbonate, and brine. The organic solution is dried (MgSO₄), filteredand concentrated to give a yellow oil. Purification by preparative HPLC(silica, hexane:ethyl acetate 4:1) yielded: (1) the less polar isomer,229 mg (18%) and (2) the more polar isomer, 248 mg (20%), both as dryfoams.

The more polar isomer (235 mg, 0.353 mmol) is heated at reflux in asolution of ethanol (4 mL) and 5N NaOH (2 mL) for 24 hours under argonatmosphere. The solution is cooled and acidified to pH 9 usingconcentrated HCl causing some white solid to form. The entire mixture isloaded onto a flash chromatography column packed with C₁₈ silica (40 mL)which had been prepared as described in the(R*,S*)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, disodium salt experiment. Isolation of the product is accomplishedin the same manner as was previously described. The product (singleenantiomer), a white powder (117 mg, 71%) is obtained. The otherenantiomer is obtained by a similar hydrolysis of the less polardiastereomer.

EXAMPLE 9 (R,R)-1,3-Benzodioxole-2,2-dicarboxylic acid,5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl) amino)propyl)-, disodium salt

A mixture of 25 g of L-DOPA, 27.7 g of di-t-butyl dicarbonate in 300 mlof dimethylformamide is heated at 65° C. for 22 hours, cooled, pouredinto 5 percent citric acid solution and extracted twice with ethylacetate. The ethyl acetate extracts are washed with brine, dried,filtered and evaporated to yield 31.0 g of(S)-N-(1,1-dimethylethoxy)carbonyl-3-hydroxy-L-tyrosine, as a brown oil.

A mixture of 31.0 g of the above t-butyl carbonate derivative, 52 ml ofiodomethane, and 145 g of anhydrous potassium carbonate in 300 ml ofacetone is heated to reflux for 20 hours, cooled, filtered and thesolvent evaporated to yield a residue. The residue is then partitionedbetween water and methylene chloride. The methylene chloride extract iswashed with brine, dried, filtered and evaporated to yield 27 g of(S)-N-(1,1-dimethylethoxy)carbonyl-3,4-dimethoxy-L-phenylalanine, methylester as a yellow solid.

A mixture of 27.0 g of the above ester derivative, 3.7 g of lithiumborohydride and 180 ml of tetrahydrofuran is allowed to react for 18hours, giving 22.0 g of(S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1-(hydroxymethyl)ethyl)carbamateas a white solid.

To an ice cold solution of 22.0 g of the above hydroxymethyl derivative,15 ml of triethylamine in 140 ml of anhydrous tetrahydrofuran, is added7.0 ml of methanesulfonylchloride, stirred at room temperature for 2hours, diluted with water, and extracted with ethyl acetate. The ethylacetate extract is washed with 2N hydrochloric acid, 1N sodiumhydroxide, brine, and then dried, filtered and evaporated to give 25.0 gof (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1-((methylsulfonyl)oxy)methyl)ethyl)carbamateas a white solid.

A mixture of 18.0 g of the above mesyl derivative and 35 ml oftrifluoroacetic acid in 80 ml of methyl chloride is reacted for 18 hoursand solvent is evaporated to yield a gray oil. The oil is dissolved inethanol and 15 g of sodium acetate, and 1.8 g of 10 percent palladium oncarbon is added. The resulting mixture is then hydrogenated on a Parrshaker overnight. The catalyst is filtered and the filtrate evaporatedto yield an oil. The oil is purified by kugelrohr distillation to yield5.8 g of (R)-3,4-dimethoxymethylbenzeneethanamine as a white solid.

A mixture of 420 mg of the above amine and 311 mg ofN-(trimethylsilyl)acetamide in 2 ml of dimethylsulfoxide is stirred atroom temperature for 1 hour. A solution of 349 mg of3-chlorostyreneoxide in 0.3 ml dimethylsulfoxide is added to the abovemixture and the resulting mixture is heated at 65° C. to 70° C. for 20hours, cooled, poured into a mixture of ice and concentratedhydrochloric acid, stirred, basified with 10N NaOH and extracted withethyl acetate. The ethyl acetate extract is washed with brine, dried,filtered and evaporated to yield an oil which is purified by flashchromatography to yield 489 mg of (R,S) and(S,S)-3-chloro-α-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl)benzenemethanol.

A mixture of 1.4 g of the above benzenemethanol derivatives, 1.39 g ofcarbonyldiimidazole, 3.5 ml of triethylamine and 15 ml oftetrahydrofuran is stirred overnight, then poured into water andextracted twice with ethyl acetate. The ethyl acetate extract is washedwith 2N hydrochloric acid, brine, dried and evaporated to an oil. Theoil is chromatographed, eluting with hexane:ethyl acetate (3:1 to 2:1).Fractions containing bottom spot are combined and evaporated giving 318mg of colorless oil. To an ice cold solution of 300 mg of this oil isadded dropwise 0.23 ml of boron tribromide. The mixture is stirred at 0°C. to 5° C. for 15 minutes, then at room temperature for 20 minutes,quenched with water and stirred for 20 minutes. The dichloromethanelayer is separated, washed with brine, dried and evaporated giving 254mg of(R,R)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinoneas a foaming solid.

A mixture of 240 mg of the above oxazolidinone, 234 mg of diethylbromomalonate, 450 mg of anhydrous potassium carbonate and 10 ml ofacetone is stirred overnight, filtered, washed with acetone andevaporated to a brown oil. The oil is purified by flash chromatography,eluting with 5 percent acetone in toluene. The pure fractions arecombined and evaporated giving 237 mg of(R,R)-5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diethyl ester as a colorless oil.

A mixture of 234 mg of the above diethyl ester, 8.5 ml of 5N sodiumhydroxide and 17 ml of ethanol is heated at reflux under argonovernight, cooled and then acidified to pH 9 using concentratedhydrochloric acid causing a copious amount of a white solid toprecipitate. The mixture is filtered and the solid is washed with water.The combined filtrate and water wash (22 ml) is loaded onto a columnpacked with C₁₈ reverse phase silica gel, which was first washed withmethanol (64 ml), and then a pH 8.5 solution. The product is elutedusing methanol:water (1:1). Evaporation of the product containingfractions gives a yellow oil which becomes a powdery solid upon theaddition of methanol. The solid is collected and washed with ether toyield 8.5 mg of the compound of this example as a white solid.

EXAMPLE 10(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diethyl ester, hydrobromide

The procedure to prepare the dimethyl ester of Example 7 is repeated,substituting ethanol for methanol to produce the compound of the exampleas a white powder, mp 174°-176° C.

EXAMPLE 11(R*,R*)-(±)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylicacid, diisopropyl ester, hydrobromide

The procedure to prepare the dimethyl ester of Example 7 is repeated,substituting 2-propanol for methanol to produce the compound of theexample as an off-white powder, mp 170°-172° C.

EXAMPLES 12-107

The procedure of Example 1 is repeated, except that the substituents onthe starting compounds are varied. Table A sets forth the compoundsproduced in accordance with the present invention.

                  TABLE A                                                         ______________________________________                                        EXAMPLE    COMPOUND                                                           ______________________________________                                        12         5-(2-((-(2,3-dichlorophenyl)-2-hydroxyethyl)                                  amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    13         5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     14         5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dibutyl ester                                     15         5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    16         5-(2-((2-(3,4-dichlorophenyl-2-hydroxy-                                       ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, diethyl ester                                   17         5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dibutyl ester                                     18         5-(2-((2-(3-bromophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester.                                   19         5-(2-((2-(3-bromophenyl-2-hydroxyethyl)                                       amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     20         5-(2-((2-(3-bromophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dibutyl ester                                     21         5-(2-((2-(3-bromophenyl)-2-hydroxyethyl)                                      amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    22         5-(2-((2-(3-bromophenyl)-2-hydroxyethyl)                                      amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, diethyl ester                                     23         5-(2-((2-(3-bromophenyl)-2-hydroxyethyl)                                      amino)butyl)-1-3-benzodioxole-2,2-di-                                         carboxylic acid, dibutyl ester                                     24         5-(2-((2-(3-fluorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    25         5-(2-((2-(3-fluorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxloe-2,2-di-                                        carboxylic acid, diethyl ester                                     26         5-(2-((2-(3-fluorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dibutyl ester                                     27         5-(2-((2-(3-fluorophenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    28         5-(2-((2-(3-fluorophenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, diethyl ester                                     29         5-(2-((2-(3-fluorophenyl)-2-hydroxyethyl)                                     amino)pentyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dibutyl ester                                     30         5-(2-((2-(3-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)propyl)-1,3-benzodioxole-                                  2,2-dicarboxylic acid, dimethyl ester                              31         5-(2-((2-(3-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)propyl)-1,3-benzodioxole-                                  2-2-dicarboxylic acid, diethyl ester                               32         5-(2-((2-(3-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)propyl)-1,3-benzodi-                                       oxole-2,2-dicarboxylic acid, dibutyl                                          ester                                                              33         5-(2-((2-(3-trifluoromethylphenyl-2-                                          hydroxyethyl)amino)butyl)-1,3-benzodioxole-                                   2,4-dicarboxylic acid, dimethyl ester                              34         5-(2-((2-(3-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)butyl)-1,3-benzodioxole-                                   2,2-dicarboxylic acid, diethyl ester                               35         5-(2-((2-(3-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)butyl)-1,3-benzodioxole-                                   2,2-dicarboxylic acid, dibutyl ester                               36         5-(2-((2-(3-methoxyphenyl)-2-hydroxyethyl)                                    amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    37         5-(2-((2-(3-methoxy-4-chlorophenyl)-2-                                        hydroxyethyl)amino)propyl)-1,3-benzodioxole-                                  2,2-dicarboxylic acid, diethyl ester                               38         5-(2-((2-(3-methoxyphenyl)-2-hydroxyethyl)                                    amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dibutyl ester                                     39         5-(2-((2-(3-methoxyphenyl)-2-hydroxyethyl)                                    amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    40         5-(2-((2-(3-methoxyphenyl)-2-hydroxyethyl)                                    amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, diethyl ester                                     41         5-(2-((2-(3-methoxyphenyl)-2-hydroxyethyl)                                    amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dibutyl ester                                     42         5-(2-((2-(3-methylphenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    43         5-(2-((2-(3-methylphenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     44         5-(2-((2-(3-methylphenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dibutyl ester                                     45         5-(2-((2-(3-methylphenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    46         5-(2-((2-(3-methylphenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, diethyl ester                                     47         5-(2-((2-(3-methylphenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dibutyl ester                                     48         5-(2-((2-(3-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, dimethyl ester                                  49         5-(2-((2-(3-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, diethyl ester                                   50         5-(2-((2-(3-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, dibutyl ester                                   51         5-(2-((2-(3-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, diethyl ester                                   52         5-(2-((2-(3-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, dimethyl ester                                  53         5-(2-((2-(3-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, dibutyl ester                                   54         5-(2-((2-(3-carbomethoxyphenyl)-2-hydroxy-                                    ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, dimethyl ester                                  55         5-(2-((2-(3-carbomethoxyphenyl)-2-hydroxy-                                    ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, diethyl ester                                   56         5-(2-((2-(3-carbomethoxyphenyl)-2-hydroxy-                                    ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, dibutyl ester                                   57         5-(2-((2-(3-carbomethoxyphenyl)-2-hydroxy-                                    ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, dimethyl ester                                  58         5-(2-((2-(3-carbomethoxyphenyl)-2-hydroxy-                                    ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, dibutyl ester                                   59         5-(2-((2-(3-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, dimethyl ester                                  60         5-(2-((2-(3-carbomethoxyphenyl)-2-hydroxy-                                    ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, diethyl ester                                   61         5-(2-((2-(3-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, diethyl ester                                   62         5-(2-((2-(3-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, dibutyl ester                                   63         5-(2-((2-(3-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, dimethyl ester                                  64         5-(2-((2-(3-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)butyl)-1,3-benzodioxole-2,2-                                      dicarboxylic acid, diethyl ester                                   65         5-(2-((2-(3-methylthio-4-chlorophenyl)-2-                                     hydroxyethyl)amino)butyl)-1,3-benzodioxole-                                   2,2-dicarboxylic acid, dibutyl ester                               66         5-(2-((2-(3-cyanophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    67         5-(2-((2-(3-cyanophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     68         5-(2-((2-(3-cyanophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dibutyl ester                                     69         5-(2-((2-(3-cyanophenyl)-2-hydroxyethyl)                                      amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    70         5-(2-((2-(3-cyanophenyl)-2-hydroxyethyl)                                      amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, diethyl ester                                     71         5-(2-((2-(3-cyanophenyl)-2-hydroxyethyl)                                      amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dibutyl ester                                     72         5-(2-((2-(2-chlorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    73         5-(2-((2-(2-chlorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     74         5-(2-((2-(2-bromophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    75         5-(2-((2-(2-bromophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dipropyl ester                                    76         5-(2-((2-(2-fluorophenyl-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    77         5-(2-((2-(2-fluorophenyl-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     78         5-(2-((2-(2-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)propyl)-1,3-benzo-                                         dioxole-2,2-dicarboxylic acid, dimethyl                                       ester                                                              79         5-(2-((2-(2-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)propyl)-1,3-benzo-                                         dioxole-2,2-dicarboxylic acid, diethyl                                        ester                                                              80         5-(2-((2-(2-methoxyphenyl)-2-hydroxyethyl)                                    amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    81         5-(2-((2-(2-methoxyphenyl)-2-hydroxyethyl)                                    amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     82         5-(2-((2-(2-methylphenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    83         5-(2-((2-(2-methylphenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, diethyl ester                                     84         5-(2-((2-(2-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, dimethyl ester                                  85         5-(2-((2-(2-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)propyl)-1,3-benzodioxole-2,2-                                     dicarboxylic acid, diethyl ester                                   86         5-(2-((2-(2-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)propyl)1-3,-benzodioxole-2,2-                                     dicarboxylic acid, dimethyl ester                                  87         5-(2-((2-(2-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)propyl)1-3,-benzodioxole-2,2-                                     dicarboxylic acid, diethyl ester                                   88         5-(2-((2-(2-ethoxyphenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    89         5-(2-((2-(2-ethoxy-3-chlorophenyl)-2-                                         hydroxyethyl)amino)propyl)-1,3-benzodioxole-                                  2,2-dicarboxylic acid, diethyl ester                               90         5-(2-((2-(4-chlorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acrd, dimethyl ester                                    91         5-(2-((2-(4-chlorophenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    92         5-(2-((2-(4-iodophenyl)-2-hydroxyethyl)                                       amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    93         5-(2-((2-(4-iodophenyl)-2-hydroxyethyl)                                       amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    94         5-(2-((2-(4-fluorophenyl)-2-hydroxyethyl)                                     amino)propyl)-1,3-benzodioxole-2,2-di-                                        carboxylic acid, dimethyl ester                                    95         5-(2-((2-(4-fluorophenyl)-2-hydroxyethyl)                                     amino)butyl)-1,3-benzodioxole-2,2-di-                                         carboxylic acid, dimethyl ester                                    96         5-(2-((2-(4-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)propyl)-1,3-benzo-                                         dioxole-2,2-dicarboxylic acid, dimethyl                                       ester                                                              97         5-(2-((2-(4-trifluoromethylphenyl)-2-                                         hydroxyethyl)amino)butyl)-1,3-benzo-                                          dioxole-2,2-dicarboxylic acid, dimethyl                                       ester                                                              98         5-(2-((2-(4-methoxyphenyl)-2-hydroxyethyl)                                    amino)propyl)-1,3-benzodioxole-2,2 di-                                        carboxylic acid, dimethyl ester                                    99         5-(2-((2-(4-methoxyphenyl)-2-hydroxyethyl)                                    amino)butyl)-1,3-benzodioxole-2,2 di-                                         carboxylic acid, dimethyl ester                                    100        5-(2-((2-(4-ethylphenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2 di-                                        carboxylic acid, dimethyl ester                                    101        5-(2-((2-(4-ethylphenyl)-2-hydroxyethyl)                                      amino)butyl)-1,3-benzodioxole-2,2 di-                                         carboxylic acid, dimethyl ester                                    102        5-(2-((2-(4-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)propyl)-1,3-benzodioxole-2,2                                      dicarboxylic acid, dimethyl ester                                  103        5-(2-((2-(4-dimethylaminophenyl)-2-hydroxy-                                   ethyl)amino)butyl)-1,3-benzodioxole-2,2                                       dicarboxylic acid, dimethyl ester                                  104        5-(2-((2-(4-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)propyl)-1,3-benzodioxole-2,2                                      dicarboxylic acid, dimethyl ester                                  105        5-(2-((2-(4-methylthiophenyl)-2-hydroxy-                                      ethyl)amino)butyl)-1,3-benzodioxole-2,2                                       dicarboxylic acid, dimethyl ester                                  106        5-(2-((2-(4-cyanophenyl)-2-hydroxyethyl)                                      amino)propyl)-1,3-benzodioxole-2,2-di-                                        dicarboxylic acid, dimethyl ester                                  107        5-(2-((2-(4-cyanophenyl)-2-hydroxyethyl)                                      amino)butyl)-1,3-benzodioxole-2,2-di-                                         dicarboxylic acid, dimethyl ester                                  ______________________________________                                    

The above mentioned patents and publications are incorporated herein byreference.

Many variations of the present invention will suggest themselves tothose who are skilled in the art in light of the above detaileddescription. All such obvious modifications are within the full intendedscope of the appended claims.

We claim:
 1. A process for producing a desired substantially pure, R,R,isomer of a compound of formula I ##STR41## wherein R₁ and R₄ may be oneor more groups which may be the same or different and are selected fromthe group consisting of hydrogen, C₁ to C₄ alkyl, C₁ to C₄ alkoxy,hydroxy, halogen, trifluoromethyl, carboxy, hydroxyalkyl,alkoxycarbonyl, C₁ to C₄ thioalkyl, sulfonyl and sulfinyl; X is adivalent radical consisting of ##STR42## wherein R' is hydrogen, R₂ andR₃ may be the same or different and are selected from the groupconsisting of hydrogen and C₁ to C₄ alkyl; R₅ and R₆ are selected fromthe group consisting of hydrogen, carboxy, alkoxycarbonyl,hydroxymethyl, --CH₂ OCH₂ COOR₇ and --CH₂ OCH₂ CH₂ OR₇ where R₇ ishydrogen or C₁ to ₄ alkyl; except that R₅ and R₆ may not both behydrogen; and the asterisks denote asymmetric carbon atoms; said processcomprising the steps of:(a) reacting Mosher's acid with a compound offormula I to attach a group of the formula ##STR43## at the N-9 positionof a mixture of (+) and (-) enantiomers of said compound to form a newpair of diastereoisomers; and (b) separating said new pair ofdiastereoisomers by HPLC and recovering the R,R isomer.